BTK inhibitors are an effective therapy for previously untreated patients with CLL but require indefinite duration treatment that can result in cumulative toxicities. Novel combinations of agents that provide deep remissions could allow for fixed duration therapy. Acalabrutinib, unlike ibrutinib, does not inhibit anti-CD20 monoclonal antibody dependent cellular phagocytosis, making it a suitable partner drug to rituximab. Using standard dosing (375mg/m2) of rituximab causes loss of target membrane CD20 immune cells and exhaustion of the finite cytotoxic capacity of the innate immune system. Alternatively, using high frequency, low dose (HFLD), subcutaneous rituximab limits loss of CD20 and allows for self-administration at home by patients. The combination of HFLD rituximab 50mg given twice a week for six cycles of 28 days with the addition of acalabrutinib starting in week 2 was evaluated in a phase II study (#NCT03788291 at clinicaltrials.gov) of 38 patients with treatment naive CLL. Patients achieving a complete response with undetectable MRD after 12 or 24 cycles of acalabrutinib could stop therapy. All patient responded, including one with a complete response with undetectable MRD in the peripheral blood and bone marrow at 12 months who stopped therapy. At a median follow-up of 2.3 years two patients with high-risk features have progressed while on acalabrutinib monotherapy. We conclude that HFLD rituximab in combination with acalabrutinib is an effective and tolerable self-administered home combination that provides a platform to build upon future regimens that may more reliably allow for fixed-duration therapy.
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